Alpha, alpha diaryl piperidino ethanols



United States Patent 2,874,161 ALPHA,ALPHA DIARYL PIPERIDINO ETHANOLS' Marcus G. Van Campen, Jr., Wyoming, and Charles H; Tilford, Cincinnati, Ohio, assignors to The Wm. S. Merrell Company, Cincinnati, Ohio, a corporation of Delaware No Drawing. Application March 7, 1952 Serial No. 275,470

2 Claims. (Cl. 260-294.7)

relatively low toxicity. The new compounds may be represented by the formula R. s omommorr in which R is hydrogen or methyl, R is an alkyl group having 1 to 3 carbon atoms, R is phenyl, lower alkoxyphenyl, lower alkylphenyl-or halophenyl, and R is phenyl, lower alkoxyphenyl, lower'alkylphenyl or halophenyl. These compounds may be prepared as free bases oras acid addition salts, and will ordinarily be used in the form of acid addition salts, such as the hydrochloride, hydrobromide, or salt with other acid.

: ,Many oflthe compounds are conveniently preparedby quaternizing the corresponding pyridinium derivative of the formula i followed by catalytic reduction or by reducing the pyridinium compound to the piperidine compound and then quaternizing. Others are more conveniently prepared by reaction of the corresponding phenacyl l-alkyl-piperidine with a Grignard reagent, e. g.,

Preparation of the compounds will be illustrated by the following specific examples, but the invention is not limited thereto.

EXAMPLE 1' Alpha,alpha-diphenyl-beta-[Z-(1-methylpiperidine)] ethanol To a Grignard solution prepared in the conventional method from 14 g. (0.09 mole) of bromobenzene, 2.3 g. (0.1 mole) magnesium turnings, and 200 ml. of dry ether was added a solution of g. (0.046 mole) of Z-phenacylice -. lamethyl-piperidine in 100 ml. of dry ether. The mixtur was refluxed 30 minutes, treated with a saturated solution of ammonium chloride, and extracted with 500 ml. of petroleum ether (40-60). The extract was evaporated on the steam bath to a volume of 50 ml., cooled, and

7 filtered; yield: 6 grams of white crystals of free base melting at 121-2. A sample was converted to a hydrochloride. Part of the crude product when recrystallized from butanone-methanol melted at 218-220. The other part of the crude hydrochloride when recrystallized from f ethanol melted at 231-2; when this was recrystallized from butanone-methanol, the melting point was 219-221.

' EXAMPLE II Alpha,alpha-diphenyl-beta-[4-(l-methylpiperidinefl j ethanol Alpha,alpha-diphenyl-4-pyridine ethanol was obtained bythe method of-Tchitchibabine (Rec. trav/Chim. 57), 582 (1938)), using gamma-picoline. The hydrochloride meltedat 263-4 dec. The free base from this hydrochloride (7. g.) in 50 ml. of methanol was heated at in a closed container with 7 ml. of 57% methyl bromide in methanol for 5 days. The reaction mixture was diluted with 2 volumes of ethyl ether, cooled, and filtered to give white crystals of alpha,alpha-diphenyl-4- pyridine ethanol methobromide melting at l91- -3. A

mixture of 8 g. (0.21 mole) of this methobromide, 0.5 g. platinum oxide catalyst, and 50 ml. of methanol was subjected to hydrogenation by shaking with hydrogen at'room temperature with an initial hydrogen pressure of 60 pounds until the theoretical amount of hydrogen was absorbed. The mixture was then warmed on a steam bath;

and the catalyst removed by filtration. The desired product as the hydrobromide was obtained as white crystals.

meltingv at 205-7 by cooling the filtrate.

EXAMPLE III Alpha,alphtz-ii-p-anisyl-beta-[Z-(1-methylpiperidine)] ethanol' A1pha,alpha di p anisyl beta (2-pyridine)ethanol was prepared by the method of Tchitchibabine using alpha-picoline and di-p-anisyl ketone as starting materials. The product obtained had an M. P. of 111-1 12 C. and its hydrochloride an M. P. of 207-208". This base was converted to the methobromide by heating at 75 in a closed container with an excess of methyl bromide in methanol for about 5 days as in Example 11 above. The product melted at 237-240. Hydrogenation of this methobromide in methanol according to the procedure of Example 11 above gave the desired dianisyl 2-(1- methylpiperidine)ethano1hydrobromide, M. P. 202-204.

EXAMPLE IV Alpha,alpha-diphenyl-beta-[Z-(1 -p'ropylpiperidine)] ethanol EXAMPLE V Alpha,alpha-diphenyl-beta-[Z-(I,6-dimethylpiperidine)] ethanol Alpha,alpha diphenyl beta [2 (6 methylpyridine)] EXAMPLE VI Alpha-phenyl-alpha-p-chlorbphenyl-beta-[Z (1- mcthylpiperiaine) lethanol Alpha phenyl alpha p chlorophenyl- 2 pyridine ethanol was obtained by the method of Tchitchibabine using 4-chlorobenzophenone in place of benzophenone. The base melted at Ill-112 and the hydrochloride at 2l3-215 C. This base was converted to the methobromide salt by the procedure of Example II, M. P. 195- 198 C. Hydrogenation of this methobromide by the method of Example II gave the desired alpha-phenylalpha-p chlorophenyl beta [2 (1 methylpiperidine)] ethanol hydrobromide, M. P. 147-150 C. This product can exist as two racemic mixtures. We have not attempted to distinguish between or separate these sterioisomers.

EXAMPLE VII Alpha,alpha-ali-p-tolyl-beta-[2-(1-methylpiperia ine)1 ethanol Alpha,alpha-di-p-tolyl-beta-(2-pyridine)ethanol was obtained by the method of Tchitchibabine using di-p-tolyl ketone in place of benzophenone. The hydrochloride had an M. P. of 193-195" C. (dec.) and the base an M. P. of 137-139 C. This base was converted to the methobromide by the procedure of Example II. The product melted at 281-283" C. (dec.). Hydrogenation of this methobromide by the procedure of Example II gave the desired di-p-tolyl l-methylpiperidine ethanol as the hydrobromide salt, M. P. 177-180 C. Use of p-cumyl-phenyl ketone in place of di-tolyl ketone gives the corresponding alpha-p-cumyl-alpha-phenyl-beta[2-(1- methylpiperidine) ]ethanol.

Thus, the invention includes compounds of the formula given above in which R is an alkyl group having 1 to 3 carbon atoms and R and R are chosen from the group which includes phenyl, lower alkoxyphenyl, lower alkylphenyl and halophenyl, with the proviso that if one or both be alkylphenyl or alkoxyphenyl, the alkyl or alkoxy group contains not more than 3 carbon atoms, that is the total number of carbon atoms in the radical does not exceed 9.

We claim:

1. Compounds of the formula R1 S CHzCRaRlOH in which R is selected from the group consisting of hydrogen and methyl, R is an alkyl group having from 1 to 3 carbon atoms, R is a radical selected from the group of phenyl, p-alkoxyphenyl, p-alkylphenyl, and p-chlorophenyl and R is a radical selected from the group consisting of phenyl, p-alkoxyphenyl, p-alkylphenyl, and p-chlorophenyl, with the proviso that the number of carbon atoms in each of the radicals R and R does not exceed 9 and with the further proviso that the CH CR R OH group is attached to the piperidine ring in one of the positions alpha and gamma.

2. Alpha,alpha-diphenyl-beta- [2-( 1-methylpiperidine)] ethanol.

References Cited in the file of this patent UNITED STATES PATENTS 1,980,638 Scheuing et al. Nov. 13, 1934 2,624,739 Werner et al. Jan. 6, 1953 2,649,444 Barrett Aug. 18, 1953 2,680,115 Ruddy June 1, 1954 OTHER REFERENCES Denton et al.: Jour. Am. Chem. Soc., vol. 71, pages 2050-56, Dec. 10, 1948.

Marvel et al.: J. A. C. 8., vol. 51, pages 915-17 (1929).

Tilford et al.: J. A. C. 8., vol. 70, pages 4001-9 (1948). 

1. COMPOUND OF THE FORMULA 